Activin A Is Anti-Lymphangiogenic in a Melanoma Mouse Model

Abstract

Melanoma spreads primarily to the sentinel lymph nodes, and its risk correlates with lymphangiogenesis, which is mainly driven by vascular endothelial growth factor (VEGF)-C. However, anti-lymphangiogenic factors are poorly characterized. We have shown in a melanoma model that Wnt1 reduces lymphangiogenesis by reducing VEGF-C expression. Screening this model for additional potentially anti-lymphangiogenic factors identified increased activin A expression and reduced expression of the antagonist, follistatin (FST), in Wnt1(+) cells. Activin A is known to reduce blood vessel formation, but the effects on lymphangiogenesis are unknown. Here we show that human primary melanoma expresses significantly higher levels of activin A and lower levels of FST compared with nevi and melanoma metastasis. Using our mouse model with melanoma cells overexpressing Wnt1, FST, Wnt1/FST, or the inhibin βA subunit (INHBA, resulting in activin A expression), we found both activin A and Wnt1 to reduce lymphangiogenesis. Whereas Wnt1 also reduced metastasis, this was not seen with activin A. In vitro, activin A phosphorylated SMAD2 in both melanoma and lymphatic endothelium but, although it reduced sprouting of lymphatic endothelium, it enhanced the migration of melanoma cells. In conclusion, activin A is an anti-lymphangiogenic factor, but because of its pleiotropic effects on cell mobility it appears not suitable as a pharmacological target.

Paracrine Activin-A signaling promotes melanoma growth and metastasis through immune evasion

“…Melanoma cell lines and tumors also frequently express Activin-A (Heinz et al, 2015, Hoek et al, 2006. Activin-A stimulates the same SMAD transcription factors as TGFβ, even though it derives from distinct precursor dimers encoded by the Inhibin βA (INHβA) gene and binds distinct complexes of the Activin/Nodal type I and II receptors Acvr1b/ALK4 or Acvr1c/ALK7 and Acvr2 (reviewed in Hedger et al, 2011, Sozzani and Musso, 2011, Walton et al, 2011.…”

“…Cytostatic and proapoptotic signaling by Activin-A has also been reported in human melanoma cell lines, although this activity is counteracted by the secreted antagonist Follistatin (FST-1) (Stove et al, 2004). Immunohistochemical analysis detected Activin-A staining in superficially spreading melanoma, whereas benign nevi and metastatic lesions showed elevated expression of Follistatin (Heinz et al, 2015). Interestingly, however, gain of transgenic Activin-A expression in the A375 human melanoma xenograft model did not alter tumor growth or metastasis, even though it reduced tumor lymphangiogenesis, a risk factor of poor prognosis (Heinz et al, 2015).…”

“…Immunohistochemical analysis detected Activin-A staining in superficially spreading melanoma, whereas benign nevi and metastatic lesions showed elevated expression of Follistatin (Heinz et al, 2015). Interestingly, however, gain of transgenic Activin-A expression in the A375 human melanoma xenograft model did not alter tumor growth or metastasis, even though it reduced tumor lymphangiogenesis, a risk factor of poor prognosis (Heinz et al, 2015). Also in xenograft models of other cancers, overexpression of a dominant negative mutant receptor revealed no adverse functions for Activin-A or related ligands, with the exception of tumor-induced systemic weight loss (cachexia) through remote Smad2,3 activation in skeletal muscles (Li et al, 2007, Zhou et al, 2010.…”

BAFF and APRIL from Activin A–Treated Dendritic Cells Upregulate the Antitumor Efficacy of Dendritic Cells In Vivo

“…For instance, in prostate and breast cancer ActA demonstrated tumor suppressive effects, while in lung and HNSCC, ActA expression correlated with increased proliferation and poor prognosis (38). ActA is also an anti-lymphangiogenic factor in melanoma (39). Although ActA levels were reported to be increased in patients with breast cancer (40) and in some mouse tumor models (41), new data showed that ActA protein in lung adenocarcinoma tissue was significantly lower than in normal lung tissue (42) and ActA may inhibit proliferation of breast cancer cell lines (43,44).…”

“…It is likely that ActA can activate autocrine and paracrine signaling affecting crosstalk between the epithelial compartment and the surrounding microenvironment (45) in a cell-type and context-dependent manner supporting or inhibiting tumor development (38). Without better understanding the controversial role of ActA in cancer, the use of ActA as a systemic pharmacological agent appears not suitable (39). At the same time, this justifies investigations into utilization of ActA potential to modulate cancer vaccines ex vivo for improving their efficacy.…”